Novel NMDA Receptor Antagonists for Beta Cell Rescue Abstract Type 2 diabetes mellitus (T2DM) is rapidly becoming the most common chronic disease in the US, with more than 7% of the adult population affected and 1.5 million new cases per year. Fundamentally, T2DM involves beta cell dysfunction and poor control of blood glucose levels, resulting in hyperglycemia. Impaired insulin secretion is accompanied by a decrease in beta cell mass, an increase in apoptosis of beta cells, and a reduced functional capacity of the remaining cells. A disease-modifying treatment would not only promote insulin secretion, but also reduce apoptosis and increase proliferation of beta cells. Recent data from animal models and Phase 2 clinical studies in humans suggest that NMDA receptors (NMDAR) inhibit insulin release and promote beta cell death and that NMDAR antagonists act as insulin secretagogues and can increase beta cell mass. Although further mechanistic studies are required to fully understand the function of NMDARs in beta cells, NMDARs may act as part of a negative feedback loop in pancreatic islets to ensure that insulin is not released in an excessive manner at high blood glucose concentrations. The lack of extreme blood glucose lowering effects with high-dose and long-term exposure to NMDAR antagonists suggests that such treatment is unlikely to lead to life-threatening hypoglycemia such as is seen with sulfonylurea treatment. The larger islet cell mass observed in diabetic mice upon long-term treatment with a high dose versus a low dose of NMDAR antagonists also indicates that inhibition of NMDARs could maintain the number of beta cells in diabetes. These data suggest that NMDAR antagonists may be useful to reduce or even reverse progression of human diabetes. Memantine, an aminoadamantane, selectively inhibits abnormally active NMDAR channels, while preserving normal activity and physiological neuronal function. Memantine has been approved for the treatment of moderate-to-severe Alzheimer's disease for over 10 years. Pathological NMDA receptor activity is further down-regulated by S-nitrosylation of specific cysteine residues. Taking advantage of these insights, PRI has developed a proprietary series of bifunctional antagonists, called nitromemantines, that not only preferentially bind to the open-channel state but also selectively target NO to a second modulatory site on the NMDAR using the memantine pharmacophore as a homing motif. During this Phase I study, we will evaluate our lead nitromemantine, YQW-036, for its activity in vitro and in an animal model of T2DM. Successful achievement of these milestones will provide a proprietary first-in-class disease-modifying drug for T2DM.